chr19-11033860-C-G

Position:

• chr19-11033860-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000344626.10(SMARCA4):​c.3868C>G​(p.Leu1290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1290P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 ENST00000344626.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.95

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21047932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3868C>G	p.Leu1290Val	missense_variant	27/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3868C>G	p.Leu1290Val	missense_variant	27/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3868C>G	p.Leu1290Val	missense_variant	27/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10	c.3868C>G	p.Leu1290Val	missense_variant	27/35	1	NM_003072.5	ENSP00000343896	P4
	ENST00000620113.1	n.134C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1290 of the SMARCA4 protein (p.Leu1290Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470370). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

The p.L1290V variant (also known as c.3868C>G), located in coding exon 26 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 3868. The leucine at codon 1290 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T;T;T;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	.;.;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.63	N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.23	N;.;N;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.21	T;.;T;.;.;.
Sift4G	Benign	0.91	T;.;T;T;.;.
Polyphen		0.46	P;P;P;P;.;.
Vest4		0.24
MutPred		0.32		Gain of methylation at K1291 (P = 0.0335);Gain of methylation at K1291 (P = 0.0335);Gain of methylation at K1291 (P = 0.0335);Gain of methylation at K1291 (P = 0.0335);.;.;
MVP		0.76
MPC		1.5
ClinPred		0.38	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555784851; hg19: chr19-11144536;